Venclexta (venetoclax)

P1, N=32, Not yet recruiting, Northside Hospital, Inc.

P2, N=204, Recruiting, Chinese PLA General Hospital

P1, N=18, Not yet recruiting, M.D. Anderson Cancer Center

A first milestone was the discovery of ABT-263 (navitoclax), a dual BCL-2/BCL-xL inhibitor. Building on this achievement, the development of venetoclax, a highly selective BCL-2 inhibitor, marked a major breakthrough, demonstrating potent pro-apoptotic activity and clinical efficacy in several leukaemia subtypes. Despite these advances, the design of inhibitors of BCL-2 family members remains challenging, largely due to the structural characteristics of the BH3-binding groove, which is both shallow and hydrophobic, complicating the identification of molecules with optimal binding affinity and selectivity. PROTACs targeting BCL-xL may represent a promising future strategy, potentially overcoming the intrinsic limitations of small molecule inhibitors.

Here, we analyzed the sensitivity of T-ALL to inhibitors of BCL-2 (venetoclax), BCL-XL (A1331852), MCL-1 (AZD5991) and dual inhibition of BCL-2/BCL-XL (AZD4320) and evaluated their combination effects with natural killer (NK) cells. Importantly, NK cell-mediated killing could be further enhanced by combining NK cells with AZD4320, proposing this combination as a potential effective treatment. Taken together, we demonstrated promising potential of BH3-mimetics and NK cells for the treatment of T-ALL alone and in combination, warranting further preclinical and potential clinical evaluation.

P1, N=155, Recruiting, Janssen Research & Development, LLC | N=100 --> 155

The main causes for these limitations include profound genomic instability, loss of p53 pleotropic function, an immunosuppressive and exhausted marrow microenvironment, a shift away from BCL-2 dependence, defects in the post-mitochondrial executioner phase of apoptosis, lineage plasticity and monocytic differentiation, upregulation of fatty acid metabolism, and BCL-2 family gene mutations. In the present review, we discuss the pathobiology of the BCL-2 family of proteins in TP53-mutated AML, mechanisms of venetoclax/BCL-2 inhibitor resistance in this molecular subset, and emerging strategies to potentially overcome this deficiency to guide therapeutic management for a population of patients who are in critical need of progress.

P1, N=3, Terminated, Weill Medical College of Cornell University | N=38 --> 3 | Trial completion date: Dec 2028 --> Feb 2026 | Recruiting --> Terminated | Trial primary completion date: Dec 2026 --> Feb 2026; Low accrual

P2, N=61, Not yet recruiting, First People's Hospital of Hangzhou

P2, N=200, Recruiting, Chinese PLA General Hospital | Trial completion date: Jan 2026 --> Jan 2030 | Trial primary completion date: Jan 2026 --> Jan 2029

The ROCKi (Fasudil, DJ4, GSK269962A) synergized with VEN to enhance cytotoxicity in both VEN-sensitive and VEN-resistant cell lines in vitro. Mechanistically, GSK augmented venetoclax responses by downregulating anti-apoptotic proteins (BCL2, MCL1) and inducing pro-apoptotic mediators (NOXA, MCL1 short isoforms), including in VEN-resistant AML cells. Together, these findings across multiple preclinical AML models demonstrate synergistic antileukemic activity and support combining VEN with ROCKi as a promising therapeutic strategy for AML.